17-Aralkyl-6 beta-azido-4,5 alpha-epox-ymorphinan-3-01{hu s

ABSTRACT

The present invention relates to novel 17-aralkyl-6 Beta -azido4,5 Alpha -epoxymorphinan-3-0ls having the following structural formula:   IN WHICH R1 is phenyl lower alkyl such as, for example, phenethyl. These compounds are useful as analgesics and antitussive agents.

United States Patent [1 1 Melt zer [4 1 Apr. 29, 1975 17-ARALKYL-6BETA-AZlDO-4,5

ALPHA-EPOXYMORPHINAN-3-OLS [75] Inventor: Robert I. Meltzer, Rockaway,NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Aug. 31, 1973 [21] Appl. N0.: 393,378

[52] U.S. Cl 260/285; 424/260 [51] Int. Cl. CO7D 43/28 [58] Field ofSearch 260/285 [56] References Cited UNITED STATES PATENTS 5/1967 Brownct al. 260/285 Primary Examiner-Donald G. Daus Assistant E \'aminer-MaryVaughn Allvrney, Agent, or FirmAlbert H. Graddis; Frank S. Chow [57]ABSTRACT The present invention relates to novel l7-araIkyl-6B-azido-4,5a-epoxymorphinan-li-Ols having the following structuralformula:

in which R is phenyl lower alkyl such as, for example phenethyl. Thesecompounds are useful as analgesics and antitussive agents.

2 Claims, No Drawings 1 l7-ARALKYL-6-BETA-AZIDO-4,5

ALPHA-EPOX-YMORPHINAN-3-0l The present invention relates to novelmorphine derivatives and, more particularly, the present inventionrelates to l7-aralkyl-6B-azido-4,5a-epoxymorphinan- 3-ols having thefollowing structural formula:

wherein R is phenyl lower alkyl in which lower alkyl has 1 to 7 carbonatoms.

The present invention also includes within its scope pharmaceuticallyacceptable acid addition salts of these novel azidomorphine derivatives.

The compounds of this invention are useful as analgesics and antitussiveagents. They are administered parenterally or orally for the managementof pain in any of the usual pharmaceutical forms including tablets,capsules, powders, suspensions, solutions, syrups and the like.Particularly valuable formulations include sustained releasepreparations which may be compounded by any of the known procedures.Generally these compounds are effective in effecting analgesia at adosage of from about 0.1 to about 0.5 mg. per kg. of body weight. Aswith any analgesic agent, the dosage should be adjusted to the severityof the indication and the degree of response. Moreover the dose may berepeated as appropriate depending upon the nature of the particularformulation, the response and the condition of the patient.

According to the present invention the above compounds are prepared byacylating 4,5a-epoxy-morphinan-3,6oz-diol, e.g., with phenyl alkanoylchloride. The l7-acylated product is reduced with a complex metalhydride to obtain 4,5ot-epoxy-l7-R -3,6a-diol. This is reacted withtosylchloride or mesylchloride to give, e. g. 4,5a-epoxy-3,6a-ditosyloxyl 7-R -mrphinan, followed by treatment withsodium azide to yield 6B- azido-4,5a-l7-R -3-tosyloxymorphinan. The compounds of this invention are obtained by alkaline hydrolysis of thelatter product.

The starting material is disclosed in Ber., 49, 750 (1916).

A further embodiment of the present invention includes the acid additionsalts prepared from pharmaceutically acceptable non-toxic acids. Suchpharmaceutically acceptable non-toxic acid addition salts include thosederived from organic and inorganic acids such as, without limitation,hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic,acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric,embonic and like acids.

In order to further illustrate the practice of this invention, thefollowing examples are included:

EXAMPLE 1 Preparation of 4,5a-Epoxyl 7-phenacetylmorphinan3,6a-diol To asuspension of 18 g 4,5a-epoxymorphinan-3,6adiol* in 330 ml methanol andml water is added 33.3 g of potassium carbonate. This is followed by32.2 g of phenylacetyl chloride which is added over a 10 minute period,maintaining a temperature of about 25C. The resulting mixture is stirredan additional 3 hours, diluted with 2 1. water and extracted with three1 1. portions of ethyl acetate. The combined extracts are washed withtwo 200 ml portions of 1.67 N hydrochloric acid followed by 200 ml ofwater, dried, filtered and the solvent evaporated. Tetrahydrofuran isadded and the solvent is again evaporated. The resulting residue isreduced without further purification as described in example 2.

*This product is disclosed in Von Braun and Kindler Bcr., 49, 750(1916).

EXAMPLE 2 Preparation of 4,5a-Epoxyl 7-phenethylmorphinan-3 ,6a-diol To25.7 g of crude 4,5a-epoxy-l7-phenacetylmorphinan-3,6a-diol is added mlof ether. A solution of lithium aluminum hydride in 300 ml ether isadded cautiously and the mixture is refluxed for 16 hours. The reactionmixture is chilled and 750 ml of 17% hydrobromic acid are slowly added.The gum formed is isolated by decanting, filtering, mixing withmethanol, and refiltering. Concentrated ammonia is added untilprecipitation is complete. The product is filtered and dried to give14.5 g melting at 23 l23l.5C.

EXAMPLE 3 Preparation of 4,5a-Epoxy-3 ,6a-ditosyloxyl7-phenethylmorphinan To 3.77 g of 4,5a-epoxy-l7-phenethylmorphinan-3,6a-diol is added 30 ml pyridine. To this solution is then added 4.19 gof tosyl chloride in 30 ml pyridine over a 10 minute period. Thetemperature is maintained at 0C during the addition and for a further 2hours, then brought to 25C for 16 hours. The solvent is removed undervacuum and the residue slurried in a mixture of ether, water and sodiumbicarbonate until dissolved. The layers are separated and the waterextracted with fresh ether. The combined ether extracts are washed withwater, dried over magnesium sulfate, and evaporated to a residue of 5.5g of an oil. This crude material is used as is in the reaction withsodium azide described in Example 4.

EXAMPLE 4 Preparation of 6B-Azido-4,5a-epoxyl 7-phenethyl-3-tosyloxymorphinan The 5.5 g of crude 4,5a-epoxy-3,6oz-ditosyloxy-l7-phenethylm'orphinan are stirred with 120 ml of dimethylformamide, 8.06 gof sodium azide, and 19 ml of water and heated at 100C for 16 hours.After cooling, it is poured into water and extracted with four 400 mlportions of ether. The combined ether extracts are washed with water,dried and evaporated to give 4.0 g of a crude oily residue.

EXAMPLE 5 Preparation of 6B-Azido-4,5a-epoxyl 7-phenethylmorphinan-3olTo 4 g. of crude 6/3-azido-4,5a-epoxy-l7-phenethyl- 3-tosyloxymorphinanobtained in example 4 are added 50 ml of ethanol containing 3 ml of 50%sodium hydroxide solution. The reaction is then heated 20 minutes on asteam bath. The alcohol is removed and 50 ml of water is added.Saturated sodium bicarbonate is then added until precipitation iscomplete. The reaction is filtered, the solids shaken in 75 ml ether,refiltered and the ether evaporated. The residue is recrystallized from20 ml ether, giving 0.9 g. of solid showing two major compounds on asilica gel thin layer chromatography plate. The more rapidly migratingcomponent is isolated by column chromatography on silica gel usingmethanol-benzene as an eluent. One recrystallization from ether gives300 mg. of the above named compound, melting at l39l42C. There is astrong infrared band at 2090 cm". [011 170.4C. (C=l in DMF) Calcd: C,71.62; H, 6.51; N, 13.92.

Found: C, 71.09; H, 6.92; N, l4.03.

I claim: 1. A compound of the formula:

wherein R is phenyl lower alkyl in which the lower alkyl portion has 1to 7 carbon atoms and the pharmaceutically acceptable acid additionsalts thereof.

2. A compound according to claim 1 wherein said phenyl lower alkyl isphenethyl.

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 whereinsaid phenyl lower alkyl is phenethyl.